Glucocorticoid Physiology

  • Glucocorticoids refer to a class of hormones that were originally so named because they were synthesized by the adrenal cortex and had the capacity to modulate blood glucose levels. The primary endogenous glucocorticoid is cortisol produced by the adrenal cortex. There are a wide variety of synthetic pharmacological glucocorticoids far more potent that cortisol which include dexamethasone and prednisone. Here we discuss the regulation and physiological actions of glucocorticoids whereas the biochemistry of their synthesis has been covered in Adrenocortical Hormone Biosynthesis.
Basic Circuitry
  • Overview
    • Synthesis of cortisol purely depends on the presence of anterior pituitary-derived ACTH. Consequently, synthesis and release of cortisol is regulated by an extended hypothalamic-pituitary axis.
  • Hypothalamic Step
    • Hypothalamus releases CRH which stimulates the anterior pituitary.
  • Pituitary Step:
    • In response to CRH stimulation the anterior pituitary releases ACTH systemically.
  • Adrenocortical Regulation:
    • Presence of ACTH induces sufficient expression of cholesterol desmolase which then allows synthesis of endogenous cortisol in the adrenocortical zona fasciculata.
  • Overview
    • The hypothalamic-pituitary circuit above is largely regulated through negative feedback control to maintain relatively stable levels of plasma glucocorticoids. Glucocortiocoids act on both the hypothalamus and pituitary to directly inhibit release of CRH and ACTH, receptively. Importantly, exogenous glucocorticoids such as dexamethasone and prednisone also display this inhibitory effect and so their administration results in reduced release of CRH and ACTH. Beyond this basic regulatory mechanism, cortisol levels do display a daily pattern of variation described below which can be perturbed by certain acute inducers of cortisol release.
  • Daily Pattern
    • Cortisol is released in a pulsatile manner throughout the day with the largest peaks observed right before awakening. The mechanism which maintains this stable, daily variation is likely complex and appears to be dependent on our normal circadian rhythm.
  • Acute Inducers
    • Certain scenarios result in acute spikes in plasma cortisol levels which appear to be coordinated by the hypothalamic-pituitary axis described above and thus occur in response to increased pituitary release of ACTH. Common acute inducers of ACTH release include highly stressful situations which emotive or physical such as burns, Surgery, or infections. Intense hypoglycemia also results in increased levels of cortisol and is likely used as a last resort for correcting insufficient blood glucose levels as will be described more fully in the future under the blood glucose regulation page.
Physiological Actions
  • Overview
    • Proper levels of glucocorticoids are absolutely critical for life. Below we discuss only the most notable physiological actions of glucocorticoids and raise the caveat that these hormones play a large number of pleiotropic effects in diverse tissues.
  • Blood Glucose Regulation
    • Glucocorticoids coordinate a number of processes to boost blood glucose levels. These include, stimulation of hepatic gluconeogenesis and enhancement of muscle breakdown, thus liberating amino acids for hepatic gluconeogenesis. In addition, glucocorticoids reduce glucose uptake by a variety of tissues.
  • Anti-inflammatory Effects
    • Glucocorticoids are some of the most potent anti-inflammatory small molecules known and are a mainstay of iatrogenic strategies for immunosuppression. Decades of research have uncovered a large variety of molecular mechanisms by which glucocorticoids carry out their anti-inflammatory effects; however, it would be fair to say that our understanding is still incomplete.
  • Inhibition of Bone Formation
    • Glucocorticoids suppress formation of bone and this accounts for some of the most negative sequelae of pharmacological glucocorticoid administration. The molecular mechanism of this action is still poorly understood.